Coagulase-negative staphylococci, particularly Staphylococcus epidermidis is a generally avirulent commensal organism of the human skin, and is the principle etiologic agent of infections of peripheral and central venous catheters, prosthetic heart valves, artificial joints, and other prosthetic devices. S. epidermidis bacteremia has an attributable mortality rate of 10-34% and results in an excess hospital stay of 8 days, and costs an estimated $6,000.00 per case. Despite its importance as a nosocomial pathogen, relatively little is known about the pathogenesis of these infections or the virulence determinants of this organism. Initial localized infections of indwelling medical devices can lead to more serious invasive infections such as septicemia, osteomyelitis, and endocarditis. Vascular catheters are thought to become infected when microorganisms gain access to the device, and hence the blood stream, by migration from the skin surface down the transcutaneous portion of the catheter. In infections associated with medical devices, plastic and metal surfaces become coated with host plasma and matrix proteins such as fibrinogen, vitronectin and fibronectin shortly after implantation. The ability of coagulase-negative staphylococci to adhere to these proteins is of crucial importance for initiating infection. Bacterial or microorganism adherence is thought to be the first crucial step in the pathogenesis of a prosthetic device infection. A number of factors influence an organism's ability to adhere to prosthetic material. These include characteristics of the microorganism and the biomaterial, and the nature of the ambient milieu. The initial attraction between the organism and the host is influenced by nonspecific forces such as surface charge, polarity, Van der Waal forces and hydrophobic interactions. The critical stage of adherence involves specific interactions between MSCRAMM® proteins and immobilized host proteins. To date, investigation concerning the adherence of coagulase negative staphylococci to biomaterials has concerned itself primarily with the role of the extracellular polysaccharide or glycocalyx, also known as slime. Despite intensive study however, the proposed role of slime in the pathogenesis of disease or even its composition remain debated. Drewry. D. T., L Gailbraith. B. I. Wilkinson, and S. G. Wilkinson. 1990. Staphylococcal Slime: A Cautionary Tale, I. Clin. Microbiol 28; 1292-1296. Currently, extracellular slime is thought to play a role in the later stages of adherence and persistence of infection. It may serve as an ion exchange resin to optimize a local nutritional environment, prevent penetration of antibiotics into the macro-colony and protect bacteria from phagocytic host defense cells. Peters et al have shown by electron microscopy studies that extracellular polysaccharide appears in the later stages of attachment and is not present during the initial phase of adherence. Peters, O., R. Locci. and G. Pulverer. 1982. Adherence and Growth of Coagulase-Negative Staphylococci on Surfaces in Intravenous Catheters. I. Infect Dis. 65146:479-482. Hogt et al demonstrated that removal of the extracellular slime layer by repeated washing does not diminish the ability of S. epidermidis to adhere to biomaterials. Hogt. A. H., I. Dankert, I. A. DeVries. and I. Feijen, 1983. Adhesion of Coagulase-Negative Staphylococci to Bloinaterials. J. Gen. Microbial. 129:2959-2968.
Thus study of exopolysaccharide has tended little to prevention of initial adherence by the bacteria. Several other studies have identified other potential adhesins of S. epidermidis including the polysaccharide adhesion (PS/A) observed by Tojo et al. Tojo, M., N. Yamashita, D. A. Goldmann. and G. B. Pier, 1988. Isolation and Characterization of a Capsular Polysaccharide Adhesin 10 from Staphylococcus epidermidis. J. Infect. Dis. 157:713-722. The slime associated antigen at (SAA) of Christensen et al. Christensen. G. D., Barker, L. P., Manhinnes, T. P., Baddour, L. M., Simpson. W. A. Identification of an Antigenic Marker of Slime Production for Staphylococcus epidermidis. Infect Immun. 1990; 58:2906-2911.
It has been demonstrated that PS/A is a complex mixture of monosaccharides and purified PS/A blocks adherence of PS/A producing strains of S. epidermidis. In an animal model of endocarditis antibodies directed against PS/A was protective. However it is not clear whether this protective effect was specific, related to anti-adhesive effects of the antibody or due to a more generalized increase in the efficiency of opsonophagocytosis of blood borne bacteria. It has been hypothesized that each functions in different stages of the adherence process with one or more of these adhesins responsible for initial attraction while other are needed for aggregation in the macro-colonies. Despite all of these studies, factors involved in the initial adherence of S. epidermidis to biomaterials remain largely unknown and equally unknown is a practical method for preventing the first stage of infection, adherence.
One particular area where improved treatment regimens is needed is the prevention/treatment of coagulase negative staphylococcal infections in low birth weight infants (LBW) by passive immunization with SdrF mAb(s). LBW infants are defined as those infants born between 500-1500 g. Premature infants are born before a sufficient transfer of protective maternal antibodies through the placenta takes place. The combination of insufficient antibodies, blood losses for diagnostic purposes, less efficient phagocytosis, microbial intestinal overgrowth under selection pressure from antimicrobial treatment, and repeated invasion of otherwise sterile sites by indwelling catheters, are some of the reasons for the very high nosocomial infection rates in this vulnerable population.
It has been recently shown that S. epidermidis contains surface proteins structurally related to S. aureus MSCRAMMs, and numerous surface proteins from S. epidermidis have previously been disclosed, e.g., in U.S. Pat. Nos. 6,703,025 and 6,635,473, said patents incorporated herein by reference. One of these S. epidermidis proteins, called SdrF (serine-aspartate repeat protein F), has features typical of Gram-positive bacterial proteins that are anchored to the cell wall. This protein shows significant amino acid sequence homology to ClfA and ClfB from S. aureus including an 500 -amino acid-long A region, a SD dipeptide repeat region, and features required for cell wall anchoring. However, it remains a desirable object to obtain effective methods of treating and/or preventing staphylococcal infections utilizing these surface proteins, and to obtain monoclonal antibodies which recognize a large number of strains of S. epidermidis so as to be widely effective in treating and/or preventing infection. To date, monoclonal antibodies that specifically recognize SdrF, exhibit high affinity (>108 KD), and are protective in animals models of disease have not been described or suggested.